AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Microvillus atrophy is the leading cause of secretory diarrhea in the first weeks of life. A group of infants with a familial enteropathy characterized by protracted diarrhea from birth and villus hypoplastic atrophy had been described in 1978 by Davidson et al.¹ The term microvillus atrophy was first used to identify the disease in 1982. The typical clinical presentation is watery profuse secretory diarrhea starting in the first hours of life. The peak age of onset is the neonatal period. Although later-onset cases have been described, cases have never been described beyond the first few months of life.

Three variants of the disease have been identified: congenital microvillus atrophy, late-onset microvillus atrophy, and atypical microvillus atrophy.

In congenital microvillus atrophy, diarrhea starts in the first days of life and is immediately life threatening. Oral alimentation in nutritionally significant amounts is impossible. In late-onset microvillus atrophy, diarrhea starts later in life, usually in the second month. Diarrhea tends to be less severe than in the other form, and some alimentation is possible. A few cases have been termed atypical microvillus atrophy, in which the onset can be congenital or late, but the histologic picture is different.

The hallmark of the disease is the electron microscopic finding of disrupted enterocytic microvilli (ie, digitations of the apical membrane of the intestinal epithelial cell protruding into the lumen) and the appearance of characteristic inclusion vacuoles, the inner surfaces of which are lined by typical microvilli. Both lesions are seen only on electronic microscopy. In a notable percentage of consanguineous families, more than one child is affected; therefore, the disease appears to be transmitted as an autosomal recessive trait.

Pathophysiology

The pathogenesis of the disease remains unknown. Severe perturbation of the microvillar cytoskeleton may disrupt the transport of brush border components that have to be assembled at the apical membrane.

Biopsy samples from the small intestine of 2 infants with congenital microvillus atrophy were examined to analyze the membrane protein of the brush border. The samples demonstrated striking diminutions of the myosin bands. The genetic defect appears likely to cause abnormal binding of the myosin to the actin cable. In one patient with late-onset microvillus atrophy, the molecular defect involved a different protein, supposedly identified as vinculin.

Other studies have suggested an alternative hypothesis, namely that a defect in the autophagocytosis pathway² or an increase in enterocyte apoptosis and proliferation³ explains the abnormalities observed in congenital microvillous disease.

The postulated abnormality in the cytoskeleton causes a block in exocytosis, mainly of periodic acid-Schiff (PAS)–positive material (eg, polysaccharides, glycoproteins, glycolipids, neutral mucopolysaccharides). As a consequence, small secretory granules that contain a PAS-positive material accumulate in the apical cytoplasm of epithelial cells.

Substantial progress has been made in identifying the molecular nature of the secretory granules. A neutral, blood group antigen–positive glycosubstance that contains acetylated sialic acid accumulates in these granules. Acetylated sialic acid has been identified as a common component of the glycocalyx, suggesting that microvillus atrophy involves a defect in exocytosis of the glycocalyx or some of its components. To support this possibility, immunoreactivity against glycocalyx is found in secretory granules in microvillus atrophy.

The microvilli in the brush border are scanty, disorganized, and short.

Because of these alterations, mature enterocytes inefficiently absorb ions and nutrients, causing a malabsorption syndrome; however, the diarrhea is caused mainly by active secretion of water and electrolytes in the intestinal lumen (secretory diarrhea). The pathogenesis of the secretory diarrhea is unknown; it is assumed to result from an unbalance between decreased absorption and unaltered secretion. Data suggest that the morphologic changes of the disease result in a secondary decrease in the amount of messenger RNA (mRNA) encoding for apical membrane-transport systems.

Frequency

United States

A cluster of cases from the Navajo reservation in northern Arizona suggests an incidence as high as 1 case per 12,000 live births.

International

A survey completed in 1987 among centers known for their involvement in pediatric gastroenterology identified more than 30 cases worldwide. Additional cases were later published. Typical congenital microvillus atrophy accounts for 80% of cases. The remaining 20% are due to mainly late-onset disease.

Mortality/Morbidity

The survival of patients with typical cases depends on total parenteral nutrition (TPN).

• Most infants of early series died when aged 3-9 months. The leading causes of death were dehydration, malnutrition, and sepsis.
• Successful outcomes of small intestinal transplantation have been reported, and evidence suggests that an early transplant might be beneficial.^{4, 5, 6}
• However, the prognosis remains poor, with most patients dying by the second decade of life as a result of complications of parenteral alimentation. Even patients who have undergone small-bowel transplantation have a mean 5-year survival rate of about 50%. Patients with late-onset microvillus atrophy appear to have an improved prognosis.

Sex

A female preponderance has been observed among the published cases, with a female-to-male ratio of 2:1.

Age

The classic form of congenital microvillus atrophy appears in the first 72 hours of life (usually on the first day) and is immediately life threatening. Late-onset microvillus atrophy starts after 6-8 weeks in a normal-appearing infant.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Pregnancy and birth are usually normal in individuals with microvillus atrophy, and polyhydramnios is usually absent, in contrast to the clinical picture of patients with other causes of congenital secretory diarrhea.

• Severe diarrhea typically appears in the first days of life, usually within the first 72 hours, but a late-onset form is also known, with onset at 6-8 weeks of age.
• The stools are watery, and the stool output is 100-500 mL/kg/d when the infant is fed, a volume comparable to or higher than that observed in cholera.
• The diarrhea is of secretory type; therefore, it persists at a stable rate of 50-300 mL/kg/d despite fasting, and the electrolyte content of the stools is increased, without an osmotic gap. However, the mucosal atrophy causes osmotic diarrhea. For this reason, alimentation increases the fecal output.
• The infant rapidly becomes dehydrated unless vigorous intravenous rehydration is started.
• Microvillus atrophy is usually characterized by growth retardation and some developmental delay later in infancy. Associated abnormalities include Meckel diverticula, abdominal adhesions, inguinal hernias, renal dysplasia, an absent corpus callosum, and hydronephrosis.
• Microvillus atrophy has been reported in association with Down syndrome and aganglionic megacolon.

Physical

• The infant appears severely dehydrated.
• Growth retardation and some developmental delay are usually present.
• No other specific findings can be detected. However, the disease is associated with other abnormalities, including Meckel diverticulum, mesenteric duct remnants, craniosynostosis, abnormal vertebrae, an absent corpus callosum, and hydronephrosis.

Causes

• Microvillus atrophy is an autosomal recessive disease, the pathogenesis of which remains unclear.
• In contrast to other congenital secretory diarrheas, polyhydramnios has not been noticed. This suggests that some environmental factor triggers the disease in a newborn who previously apparently healthy.
• At least 5 patients with congenital microvillus atrophy have presented clinical and laboratory findings suggestive of dihydropyrimidinase deficiency. In 2 of these patients, the enzymatic defect was demonstrated. Whether this association can be caused by a contiguous gene syndrome remains speculative.
• The clinical course of isolated dihydropyrimidinase deficiency varies, but most patients present with neurologic signs.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Congenital secretory diarrhea
Congenital chloride diarrhea
Congenital sodium-losing diarrhea
Bile acid malabsorption
Congenital disorders of intestinal digestive/absorptive processes
Congenital lactase deficiency
Congenital glucose and/or galactose malabsorption
Intractable diarrhea of infancy
Autoimmune enteropathy
Enterocyte membrane integrin deficiency
Other causes of intractable diarrhea
Intestinal infections

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

The following studies are indicated in patients with congenital microvillus atrophy:

• Measurements of stool electrolytes and osmolality enable rapid and accurate assessment of the pathogenesis of this important chronic diarrhea (osmolar vs secretory) and greatly narrows the differential diagnoses.
• In assessing the nature of diarrhea, remember that stool samples should be sent for electrolyte and osmolarity measurements only if patients have liquid stools.
• Fecal electrolytes demonstrate a typical pattern of secretory diarrhea.
• • Fecal sodium levels are high (approximately 60-120 mEq/L), and no osmotic gap is found.
  • In patients with secretory diarrhea, the following formula applies: 2(Na concentration + K concentration) = stool osmolarity ± 50.
  • In osmotic diarrhea, stool osmolarity exceeds 2(Na concentration + K concentration) by 100 or more.
• In osmotic diarrhea, findings on stool microscopy are negative for WBCs, blood (exudative diarrhea), and fat (steatorrhea).
• Secretory diarrhea occurs in the fasting state and is associated with large output losses that cause dehydration and metabolic acidosis.
• The stool culture is likely negative in prolonged diarrhea, as well as in a diarrhea that lacks blood, a finding that suggests no invasive bacteria.
• Serum electrolyte levels may be very useful in the management but add little information to establish a diagnosis.
• The D-xylose test is of little value at early ages and lacks specificity. In severe diarrhea, results are likely to be false-positive because of the fast transit time.
• Pancreatic enzymes are rarely measured in pediatric patients.
• Cystic fibrosis, the most common cause of pancreatic insufficiency, is best confirmed or ruled out by performing the sweat test.

Other Tests

• Duodenal biopsy
• • Findings from duodenal biopsy must not be considered diagnostic.
  • Histologic results of duodenal biopsy samples can range from essentially normal to mildly abnormal, showing the following:
  • • Thin mucosa caused by hypoplastic villus atrophy
    • Diffuse villus atrophy (loss of villus height)
    • Crypt hypoplasia
  • The diagnosis rests on findings demonstrated by electron microscopy (see Histologic Findings).
• Rectal biopsy
• • Findings demonstrate microvillous involutions and an increased number of secretory granules.
  • This test has been proposed as a relatively easy method for making an early diagnosis.

Histologic Findings

• Electron microscopy demonstrates well-preserved crypt epithelium with abundant microvilli. Villus enterocytes are severely abnormal, particularly toward the apices of the short villi. The microvilli are depleted in number, short, and irregularly arranged. Some of the enterocytes contain the typical microvillus involutions, which are intracellular vacuoles where microvilli are observed lining the inner surface. A striking feature is a number of small, membrane-bound vesicles containing electron-dense material.
• A few cases have been described in which the classic microvillous inclusions are shadowed by other features, such as large aggregates of electron lucent, vermiform membranous vesicles in enterocyte cytoplasm.^{7, 8}
• PAS staining of the intestinal biopsy sample reveals PAS-positive material in the apical cytoplasm. The normal linear staining of the glycocalix is absent. PAS accumulates in low crypts in atypical microvillus atrophy, in upper crypts in congenital microvillus atrophy, and in low villi in late-onset microvillus atrophy.
• Anti-CD10 immunohistochemistry shows a marked enlargement of the stained band that appears doubled compared with controls.^{9, 10} CD10 is a neutral membrane-associated peptidase; thus, abnormal stain findings with PAS or anti-CD10 immunohistochemistry are expressions of the abnormalities in microvillar structure.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Several drugs have been tried to counteract the massive secretory diarrhea in patients with microvillus atrophy; however, none has proven effective. At present, the only available therapy is total parenteral nutrition (TPN).

• Agents tentatively given to induce a better growth of the intestinal mucosa (eg, epithelial growth factor, colostrum) are ineffective.
• Antisecretagogue agents (eg, somatostatin, octreotide, loperamide, chlorpromazine) can reduce the stool output, but the clinical significance of this effect is marginal.

Surgical Care

• Successful transplantation of the small intestine may allow for the patient's survival without TPN.
• Transplantation appears to be the only option for patients who do not fare well with long-term TPN (eg, because of sepsis, liver damage, lack of vascular access).
• Although only small series have been reported, evidence suggests that early small-bowel transplantation should be performed.
• The current survival rate for children with microvillus atrophy who undergo transplantation remains around 50% at 5 years.

Diet

• In most patients with early-onset microvillus atrophy, no intake by mouth is possible. In the late-onset variant, minimal oral intake may be possible.
• Except for rare, documented exceptions, no improvement of the condition is observed. Food intolerance remains complete in the overwhelming majority of patients described.
• Long-term nutritional support is accomplished with TPN.
• For patients in whom transplantation is successful, a gradual return to a normal diet is considered possible.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Several drugs, including epidermal growth factor, octreotide, glutamine, and chlorpromazine, have been tried to counteract the massive secretory diarrhea in patients with microvillus atrophy. However, none have been proven effective.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• The prognosis is poor. If patients are untreated, the disease is rapidly fatal because of dehydration and malnutrition.
• If patients are treated with total parenteral nutrition (TPN), their prognosis entirely depends on the complications of this approach. These complications include cholestasis with subsequent liver damage leading to cirrhosis, catheter-related sepsis due to infection with bacterial or fungal agents, and progressive lack of vascular access.
• The limited experience accumulated in a few centers worldwide reflects an overall survival rate of approximately 50% at 5 years after small-bowel transplantation; this is a much better outcome than is seen with other indications for intestinal transplantation.⁶
• Children with late-onset congenital microvillous atrophy usually have less severe diarrhea; with age they can reduce the requirements of TPN to 1-2 per week.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose congenital microvillus atrophy

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Davidson GP, Cutz E, Hamilton JR, Gall DG. Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy. Gastroenterology. Nov 1978;75(5):783-90. [Medline].
2. Reinshagen K, Naim HY, Zimmer KP. Autophagocytosis of the apical membrane in microvillus inclusion disease. Gut. Oct 2002;51(4):514-21. [Medline].
3. Groisman GM, Sabo E, Meir A, Polak-Charcon S. Enterocyte apoptosis and proliferation are increased in microvillous inclusion disease (familial microvillous atrophy). Hum Pathol. Nov 2000;31(11):1404-10. [Medline].
4. Herzog D, Atkison P, Grant D, et al. Combined bowel-liver transplantation in an infant with microvillous inclusion disease. J Pediatr Gastroenterol Nutr. May 1996;22(4):405-8. [Medline].
5. Oliva MM, Perman JA, Saavedra JM, et al. Successful intestinal transplantation for microvillus inclusion disease. Gastroenterology. Mar 1994;106(3):771-4. [Medline].
6. Ruemmele FM, Jan D, Lacaille F, et al. New perspectives for children with microvillous inclusion disease: early small bowel transplantation. Transplantation. Apr 15 2004;77(7):1024-8. [Medline].
7. Weeks DA, Zuppan CW, Malott RL, Mierau GW. Microvillous inclusion disease with abundant vermiform, electron-lucent vesicles. Ultrastruct Pathol. Sep-Oct 2003;27(5):337-40. [Medline].
8. Iancu TC, Mahajnah M, Manov I, Shaoul R. Microvillous inclusion disease: ultrastructural variability. Ultrastruct Pathol. May-Jun 2007;31(3):173-88. [Medline].
9. Groisman GM, Amar M, Livne E. CD10: a valuable tool for the light microscopic diagnosis of microvillous inclusion disease (familial microvillous atrophy). Am J Surg Pathol. Jul 2002;26(7):902-7. [Medline].
10. Youssef N, M Ruemmele F, Goulet O, Patey N. [CD10 expression in a case of microvillous inclusion disease]. Ann Pathol. Dec 2004;24(6):624-7. [Medline].
11. Assmann B, Hoffmann GF, Wagner L, et al. Dihydropyrimidinase deficiency and congenital microvillous atrophy: coincidence or genetic relation?. J Inherit Metab Dis. Sep 1997;20(5):681-8. [Medline].
12. Carruthers L, Dourmashkin R, Phillips A. Disorders of the cytoskeleton of the enterocyte. Clin Gastroenterol. Jan 1986;15(1):105-20. [Medline].
13. Cutz E, Rhoads JM, Drumm B, et al. Microvillus inclusion disease: an inherited defect of brush-border assembly and differentiation. N Engl J Med. Mar 9 1989;320(10):646-51. [Medline].
14. Michail S, Collins JF, Xu H, et al. Abnormal expression of brush-border membrane transporters in the duodenal mucosa of two patients with microvillus inclusion disease. J Pediatr Gastroenterol Nutr. Nov 1998;27(5):536-42. [Medline].
15. Nathavitharana KA, Green NJ, Raafat F, Booth IW. Siblings with microvillous inclusion disease. Arch Dis Child. Jul 1994;71(1):71-3. [Medline].
16. Pecache N, Patole S, Hagan R, et al. Neonatal congenital microvillus atrophy. Postgrad Med J. Feb 2004;80(940):80-3. [Medline].
17. Phillips AD, Brown A, Hicks S, et al. Acetylated sialic acid residues and blood group antigens localise within the epithelium in microvillous atrophy indicating internal accumulation of the glycocalyx. Gut. Dec 2004;53(12):1764-71. [Medline].
18. Phillips AD, Jenkins P, Raafat F, Walker-Smith JA. Congenital microvillous atrophy: specific diagnostic features. Arch Dis Child. Feb 1985;60(2):135-40. [Medline].
19. Phillips AD, Schmitz J. Familial microvillous atrophy: a clinicopathological survey of 23 cases. J Pediatr Gastroenterol Nutr. May 1992;14(4):380-96. [Medline].
20. Phillips AD, Szafranski M, Man LY, Wall WJ. Periodic acid-Schiff staining abnormality in microvillous atrophy: photometric and ultrastructural studies. J Pediatr Gastroenterol Nutr. Jan 2000;30(1):34-42. [Medline].

Article Last Updated: Nov 17, 2008